Our preliminary data for (a) aryldiimides, (b) fused ring diamidines, (c) unfused aromatic ring groove binding diamidines and (d) diarylisoxazolium intercalators show that compounds of these classes are active against HIV in cell culture and that they exhibit low toxicity. Furthermore, a relationship has been observed between the anti-HIV activity and nucleic acid binding for these compounds. Potential anti-HIV agents proposed for synthesis are designed to favor interaction with HIV cytoplasmic nucleic acids as opposed to host chromosomal nucleic acids. We will attempt to take advantage of the fact that single-stranded RNA and RNA-DNA hybrids' secondary structure are thought to exist in A-form rather than in B-form helices. These nucleic acid structural differences suggest that intercalators with large bulky groups should bind more favorably to viral RNA or RNA-DNA hybrids that to host DNA. Furthermore, there is evidence that large molecules are not transported efficiently through nuclear membrane pores: thus, large bulky nucleic acid binding compounds should interact selectively with viral cytoplasmic nucleic acids. Another difference in the structure of RNA and RNA/DNA hybrids and DNA is the depth and structure of the grooves. Groove binding molecules are proposed which, with careful modification, should fit the major groove of RNA but will be too large to fit the DNA minor groove and too small to fit well into the DNA major groove. Close collaboration with the Biological Core and the Biophysical Group (Project 4) will provide rapid feedback on the effect of structure modifications on anti-HIV activity and nucleic acid binding. The coupling of this data along with molecular modeling should provide insights which will allow rapid recognition of the optimum molecule in a given system.